Studies with hyperinsulinemic clamps analogous to ours have also previously been shown selleck bio to evoke increases in circulating ET-1 (14). Although in vivo dose-response data in humans are not available, the assumption that higher levels of insulin should have produced a greater effect in obesity is supported by in vitro data demonstrating a clear dose response across the range of insulin levels we produced (14, 31). Overall, it seems likely that the insulin exposure was itself sufficient in both concentration and duration to have elicited an effect on endothelin production. Slow vasodilator responses to endothelin antagonism are well recognized, with full actions often requiring 60 min.

We provided exposure to BQ-123 throughout the 4-h duration of the insulin infusion, using an infusion rate that has been previously shown by us, using the current techniques, to demonstrate midrange vasodilation with a signal range sufficient to recognize increases in LVC of as little as 30% (29). A priori our study was designed to detect a group difference in the BQ-123-induced increase in the insulin-induced increment in LVC of ~12 units; the observed group differences of ~1 units were unequivocally negative (i.e., reflecting a true lack of effect rather than problems with statistical power). Also, as described above, the range of vasodilation responses observed was well below the maximum range of our technique. Overall, we cannot account for this unexpectedly negative result on the basis of design or technical issues. Assumptions in the hypothesis.

The notion of selective insulin resistance underlies the presumption that greater hyperinsulinemia might have induced proportionally greater ET-1 production and action. This in turn is based on the premises that 1) insulin actions to NO are affected by insulin resistance, whereas insulin actions to ET-1 are not; and 2) insulin’s actions to regulate ET-1 are direct and proportional. What is the evidence in support of these assumptions? Premise 1 appears to be well grounded. The literature contains convincing evidence from in vitro and animal studies in favor of selective insulin resistance (9, 10, 40, 41). This has been most unequivocally demonstrated in experimental circumstances where insulin’s actions via PI3-kinase are Cilengitide inhibited by wortmannin, leaving residual actions to ET-1 unaffected (9, 11, 40). Of note, only one of these studies evaluated dose-response relationships (11), and this study was done in nonobese rats. The question remains open whether this effect also applies to vessels from insulin-resistant animals. Premise 2 (whether the actions to stimulate ET-1 are proportional to hyperinsulinemia) has been evaluated in vitro but not confirmed in vivo.